-    PRODUODOPA® (foslevodopa/foscarbidopa) is the first-and-only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of advanced Parkinson's disease

-   PRODUODOPA demonstrated sustained improvements in "Off" time (when symptoms return between medication doses), "On" time (when symptoms are controlled) without dyskinesia (involuntary movement), and morning akinesia ("Off" time upon waking)

NORTH CHICAGO, Ill., Jan. 9, 2024 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced the launch of PRODUODOPA® (foslevodopa/foscarbidopa) in the European Union for the treatment of advanced Parkinson's disease with severe motor fluctuations and hyperkinesia (excessive movement) or dyskinesia (involuntary movement), and when available combinations of Parkinson's medicinal products have not given satisfactory results.1

PRODUODOPA is the first-and-only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of severe motor fluctuations in people living with advanced Parkinson's disease whose symptoms are inadequately controlled by other therapies. The continuous delivery of PRODUODOPA provides levodopa 24-hours a day which may help patients by extending the period when symptoms are well-controlled, often referred to as "On" time.2

AbbVie was granted marketing authorization of PRODUODOPA through the Decentralized Procedure in the third quarter of 2022. The VYAFUSER™ pump for the subcutaneous delivery of PRODUODOPA received Conformité Européenne (CE) Mark in November of 2023.

Parkinson's disease is a chronic, progressive neurodegenerative disorder affecting approximately 6.1 million people globally3 and is expected to double by 2040. Parkinson's disease is characterized by tremor, muscle rigidity, slowness of movement and difficulty with balance.4 As the disease progresses, the severity of symptoms increases5, and patients tend to experience greater disability and an impaired ability to perform activities of daily living6, as well as the reemergence of symptoms as standard treatment wears off.7 Characteristics of advanced Parkinson's disease may include needing help with performing daily activities, increased motor fluctuations (changes in the ability to move referred to as "On-Off" times), difficulty swallowing, recurrent falls, dementia, dyskinesia (involuntary movements) and other symptoms.5

"People living with Parkinson's disease experience daily challenges and uncertainty, especially as their disease progresses and symptoms are no longer adequately controlled," said Roopal Thakkar, Senior Vice President, Development and Regulatory Affairs and Chief Medical Officer, AbbVie. "This approval is an example of our unwavering commitment to this community by developing new, transformative therapeutic options for people experiencing advanced Parkinson's disease, their families, and care partners." 

The launch was supported by three studies: the Phase 3, 12-month open label study (M15-741 study) which evaluated the long-term safety, tolerability, and efficacy of continuous subcutaneous infusion of PRODUODOPA8, the Phase 3, 12-week study (M15-736 study) which compared the efficacy and safety of PRODUODOPA to oral levodopa/carbidopa2, and a Phase 1 pharmacokinetic comparability study.9

Findings from the M15-741 safety and tolerability study showed a favorable benefit/risk profile and demonstrated sustained improvements in "Off" time and "On" time without dyskinesia, and morning akinesia as measured by the percentage of patients in early morning "Off" time as recorded by PD diary.8

The majority of adverse events (AEs) with PRODUODOPA were non-serious and mild or moderate in severity. The most frequent AEs (greater than or equal to 10 percent) were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.1

"This approval represents a significant advancement for those with Parkinson's disease who have historically had limited treatment options for advanced stages," said Angelo Antonini, MD, PhD, Professor of Neurology at the Department of Neuroscience, University of Padua, Italy. "When oral treatment no longer sufficiently helps with improvement in motor fluctuations, patients need alternative options. PRODUODOPA's around-the-clock infusion allows for continuous delivery of levodopa, the gold standard of treatment."

"As Parkinson's progresses, it can take a significant physical and emotional toll not only on the person but also on their family and care partners, who often play a critical role in their daily lives," said Josefa Domingos, President, Parkinson's Europe. "It is vital that the Parkinson's community have more options that can help them manage their symptoms."

About the Phase 3 M15-741 Study8
The Phase 3, single arm, open-label study evaluated the safety and tolerability, and efficacy of 24-hour daily exposure of continuous subcutaneous infusion of PRODUODOPA in people with advanced Parkinson's disease whose motor symptoms were inadequately controlled by their current treatment. The primary endpoint was to evaluate the safety and tolerability of PRODUODOPA. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, and total scores from quality-of-life surveys. The study was conducted at 58 sites across 13 countries (Australia, Belgium, Canada, Denmark, Germany, Italy, Japan, Netherlands, Russia, Spain, Sweden, United Kingdom, and United States). Eligible patients included adults 30 years or older diagnosed with levodopa-responsive idiopathic Parkinson's disease experiencing an average of greater than or equal to 2.5 hours of "Off" time per day, as assessed by patient's Parkinson's disease diaries. Reduction in motor fluctuations was observed as early as one week and persisted through week 52. The percentage of patients experiencing morning akinesia dropped from 77.7 percent at baseline to 27.8 percent at week 52. Indicators of sleep and quality of life were assessed from baseline through week 52 as published in the Journal of Neurology & Therapy (https://doi.org/10.1007/s40120-023-00533-1). More information on the study can be found on www.clinicaltrials.gov (NCT03781167).

About the Phase 3 M15-736 Study2
The Phase 3 randomized, double-blind, double-dummy, active-controlled study compared the efficacy, safety and tolerability of PRODUODOPA to oral immediate-release levodopa/carbidopa (LD/CD) in patients with advanced Parkinson's disease. Participants were provided with a home diary (the PD Diary) to assess their motor state during the day. The primary endpoint was "On" time without troublesome dyskinesia. The study included 141 participants who were randomly assigned and received treatment at 65 centers in the U.S. and Australia. Participants were randomized one to one to receive either the PRODUODOPA solution as a continuous delivery under the skin (subcutaneous) plus oral placebo capsules for LD/CD or oral capsules containing immediate-release LD/CD plus continuous subcutaneous delivery of placebo solution for PRODUODOPA. The treatment duration was 12 weeks. The increase in "On" time without troublesome dyskinesia at week 12 was an average of 2.72 hours for PRODUODOPA versus 0.97 hours for oral LD/CD (p= 0.0083). Improvements in "On" time were observed as early as the first week and persisted throughout the 12 weeks. This study also assessed changes from baseline to week 12 in motor experiences of daily living, morning akinesia, sleep, and quality of life indicators, however results did not achieve statistical significance. More information on the study can be found on www.clinicaltrials.gov (NCT04380142) and in The Lancet Neurology (https://doi.org/10.1016/S1474-4422(22)00400-8). 

About the Phase 1 Pharmacokinetic study9
A Phase 1, open label, randomized, two period cross over study was conducted to compare the pharmacokinetics (PK) of levodopa from 24-hour continuous subcutaneous infusion of PRODUODOPA (foslevodopa/foscarbidopa) to the PK of levodopa from 16-hour levodopa-carbidopa intestinal gel (LCIG), followed by two night-time oral levodopa/carbidopa (LD/CD) doses. The levodopa exposures following subcutaneous infusion of PRODUODOPA over 24 hours were similar (less than 8 percent difference) to those of LCIG mg LD/CD administered over 16 hours, followed by two oral doses at 18 and 21 hours after the start of LCIG delivery. The study concluded that 24-hour continuous subcutaneous infusion of PRODUODOPA provides levodopa exposures comparable to LCIG throughout the day. More information on the study can be found on www.pubmed.ncbi.nlm.nih.gov (35339102) and in Science Direct (https://doi.org/10.1016/j.parkreldis.2022.03.012).

About PRODUODOPA® (foslevodopa/foscarbidopa)
PRODUODOPA® (foslevodopa/foscarbidopa) is a solution of levodopa and carbidopa prodrugs for 24-hour continuous subcutaneous infusion for the treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results.

PRODUODOPA® (foslevodopa and foscarbidopa solution for infusion) Indication and Summary of Important Treatment Considerations1

Indication
Treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results.

Contraindications

PRODUODOPA is contraindicated in patients with hypersensitivity to the active substances or to any of the excipients, narrow-angle glaucoma, severe heart failure, acute stroke, severe cardiac arrhythmia, co-medication with selective MAO type A inhibitors and nonselective MAO inhibitors, conditions contraindicated for adrenergics (e.g. pheochromocytoma, hyperthyroidism, and Cushing's syndrome), and suspicious undiagnosed skin lesions or history of melanoma.

Select special warnings and precautions for PRODUODOPA

Special warnings and precautions for PRODUODOPA
Several warnings and precautions below are generic for levodopa and, therefore, also for PRODUODOPA.

Not recommended for the treatment of drug-induced extrapyramidal reactions.

Caution use in patients with: severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions. History of myocardial infarction with residual atrial nodal or ventricular arrhythmias, cardiac function should be monitored during the initial dosage adjustments. Monitor all patients for the development of mental changes, depression with suicidal tendencies, and other serious mental changes. Caution with past or current psychosis and antipsychotics used concomitantly with dopamine receptor-blocking properties (observe for loss of antiparkinsonian effect). Higher frequency of hallucinations may occur with dopamine agonists and/or other dopaminergic treatments including PRODUODOPA. Monitor patients regularly for the development of impulse control disorders, for example Dopamine Dysregulation Syndrome (DDS).  Before initiation of treatment, warn patients and caregivers of the potential risk of developing DDS. The dose of PRODUODOPA may need to be adjusted downwards in order to avoid levodopa induced dyskinesias. Caution in chronic wide-angle glaucoma; monitor for intra-ocular pressure changes. PRODUODOPA may induce orthostatic hypotension and should be given cautiously in patients taking other medicinal products that may cause orthostatic hypotension. Concomitant use of selegiline and levodopa/carbidopa has been associated with serious orthostatic hypotension. Levodopa may induce somnolence and sudden sleep: caution should be exercised when driving and operating machines. Risk of symptoms resembling Neuroleptic Malignant Syndrome following abrupt dose reduction or discontinuation.

Infusion site events (see section 4.8) have been reported in patients receiving PRODUODOPA. Follow aseptic techniques and frequently rotate the infusion site to reduce the risk. In clinical studies, few patients who reported infusion site reactions also experienced infusion site infections. Therefore, monitor for serious infusion site reactions and infusion site infections.

Patients with Parkinson's disease have a higher risk of developing melanoma. Monitor patients for melanomas on a regular basis when using PRODUODOPA.

Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with PRODUODOPA.

PRODUODOPA contains hydrazine (foscarbidopa degradation product), that can be genotoxic and probably carcinogenic. The approximately median exposure of hydrazine is 0.2 mg/day, with a maximum of 0.5 mg/day. The clinical significance of this hydrazine exposure is not known.

Reduced ability to handle the delivery system can lead to complications. In such patients a caregiver should assist the patient.

A sudden or gradual worsening of bradykinesia may indicate an obstruction in the device for whatever reason and needs to be explored.

Polyneuropathy has been reported; evaluate for history/signs of and known risk factors before starting therapy.

PRODUODOPA is high in sodium; considered especially in patients on a low salt diet.

Caution is needed in concomitant administration of PRODUODOPA with the following medicinal products: Antihypertensives, antidepressants, COMT inhibitors, dopamine antagonists, MAO inhibitors, amantadine. Sympathomimetics may increase cardiovascular adverse events related to levodopa. Foscarbidopa is a potential inducer of CYP1A2 in vitro. Care should be taken when prescribing PRODUODOPA in combination with sensitive CYP1A2 substrates (e.g. caffeine). Review section of interactions with other medicinal products in SmPC for further details about these and a complete list of interactions.

Fertility, pregnancy and lactation

PRODUODOPA is not recommended during pregnancy. Breast-feeding should be discontinued during treatment with PRODUODOPA.

Undesirable effects

Summary of the safety profile

The most frequent adverse reactions (≥10%) reported in all Phase 3 studies in patients exposed to PRODUODOPA were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.

This is not a complete summary of all safety information. Globally, prescribing information varies; please refer to your country specific product labeling for complete product prescribing and safety information.

About AbbVie in Neuroscience
At AbbVie, our commitment to preserving personhood of people around the world living with neurological and psychiatric disorders is unwavering. With more than three decades of experience in neuroscience, we are providing meaningful treatment options today and advancing innovation for the future. AbbVie's Neuroscience portfolio consists of approved treatments in neurological conditions, including migraine, movement disorders, and psychiatric disorders, along with a robust pipeline of transformative therapies. We have made a strong investment in research and are committed to building a deeper understanding of neurological and psychiatric disorders. Every challenge makes us more determined and drives us to discover and deliver advancements for those impacted by these conditions, their care partners, and clinicians. For more information, visit www.abbvie.com. 

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com.

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Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions and uses of future or conditional verbs, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2022 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References

1 PRODUODOPA® (foslevodopa/foscarbidopa solution for infusion) Summary of Product Characteristics. November 2023.
2 Soileau, M., et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial. The Lancet Neurology. December 2022.
3 Armstrong, MJ. and Okun, MS. (2020). Diagnosis and Treatment of Parkinson Disease. A Review. JAMA 2020; 323(6): 548-560.
4 "What is Parkinson's?" Parkinson's Foundation. Available at: https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons. Accessed: August 29, 2023.
5 Luquin M-R et al. Parkinson's Dis. 2018; 4047392.
6 Malaty IA et al. (2022). Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries. Gainsville: BCM Neurology.
7 "Wearing off and motor fluctuations". Parkinson's Europe. Available at https://www.parkinsonseurope.org/about-parkinsons/symptoms/motor-symptoms/wearing-off-and-motor-fluctuations/#:~:text=Wearing%20off%20tends%20to%20happen,when%20medications%20will%20be%20effective. Accessed November 6, 2023.
8 Aldred, J., et al. Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study. Journal of Neurology & Therapy. August 2023.
9 Rosebraugh, M., et al. Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum. Science Direct. April 2022.  

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